Bone marrow failure and extramedullary hematopoiesis in McCune-Albright syndrome.

In fibrous dysplasia/McCune-Albright syndrome (FD/MAS), bone and bone marrow are, to varying degrees, replaced by fibro-osseous tissue typically devoid of hematopoietic marrow. Despite the extensive marrow replacement in severely affected patients, bone marrow failure is not commonly associated with FD/MAS. We present a 14-year-old girl with FD/MAS, who developed pancytopenia and extramedullary hematopoiesis (EMH) with no identified cause, in the setting of iatrogenic thyrotoxicosis and hyperparathyroidism. Pancytopenia, requiring monthly blood transfusions, persisted despite multiple strategies to correct these endocrinopathies. Due to worsening painful splenomegaly, likely as a result of sequestration, splenectomy was performed. Following splenectomy, pancytopenia resolved and patient has since been transfusion-independent. We report the first detailed case of bone marrow failure and EMH in FD/MAS. The etiology of marrow failure is likely multifactorial and related to the loss of marrow reserve due to extensive polyostotic FD, exacerbated by iatrogenic thyrotoxicosis and hyperparathyroidism. Mini Abstract: A patient with fibrous dysplasia developed bone marrow failure and extramedullary hematopoiesis. The etiology likely involved loss of hematopoetic marrow space and uncontrolled endocrinopathies. Splenectomy was therapeutic.

Successful Treatment of Ascites using a Denver® Peritoneovenous Shunt in a Patient with Paroxysmal Nocturnal Hemoglobinuria and Budd-Chiari syndrome.

A 56-year-old man was diagnosed with aplastic anemia and paroxysmal nocturnal hemoglobinuria at 43 years of age and treatment with cyclosporin A was started. Liver cirrhosis, ascites, and thrombus in the hepatic veins were found at 56 years of age and Budd-Chiari syndrome (BCS) was diagnosed according to angiography findings. He was treated with diuretics and paracentesis was performed several times, but with limited efficacy. A Denver® peritoneovenous shunt (PVS) was inserted into the right jugular vein; his ascites and renal function improved immediately and his general condition has remained good for 12 months since starting the above treatment regimen. A PVS is a treatment option for ascites due to BCS.

[Successful management of orthopedic operations requiring general anesthesia in a PNH patient after introduction of eculizumab].

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal hematopoietic stem cell disorder that presents with hemolytic anemia, thrombosis, and bone marrow failure. Stressors such as infection and pregnancy have been known to exacerbate hemolysis in PNH patients. Surgery can also trigger prominent complement activation and is an important risk factor for hemolysis. Furthermore, the postoperative thrombosis risk is high. Eculizumab, which is a humanized monoclonal antibody against C5, suppresses hemolysis and prevents thrombosis, and thus improves quality of life for PNH patients. However, few reports have focused on eculizumab-treated PNH patients undergoing surgery. We report a 79-year-old PNH patient receiving eculizumab treatment who underwent three consecutive orthopedic surgeries requiring general anesthesia. Perioperative management was carried out routinely, as in non-PNH patients, and no postoperative complications developed. Surgery was formerly considered to be a high risk event for PNH patients, but this case raises the possibility that even elderly PNH patients may undergo surgery safely when maintained on eculizumab treatment.

Bone marrow transplant for a girl with bone marrow failure and cerebral palsy.

Bone marrow transplantation (BMT) has been used with increasing frequency to treat congenital bone marrow failure syndrome (CBMFs) successfully. Decision to perform BMT, however, is difficult in the case of comorbidity because of regimen-related toxicities. We describe here a child with CBMFs, severe cerebral palsy (CP) at Gross Motor Function Classification System level V and mental retardation (MR) who was transfusion dependent despite various medications. She underwent BMT from an HLA-1 locus-mismatched unrelated donor. Although engraftment was successful, no neurological improvement was seen 5 years after BMT. While CBMFs patients who have CP and MR could undergo transplantation safely, they may not benefit neurologically from BMT.

Homing of chloromethylbenzoyl ammonia-labeled bone marrow mesenchymal stem cells in an immune-mediated bone marrow failure mouse model in vivo.

Aplastic anemia is an abnormal immune reaction disease in which T lymphocytes destroy hematopoietic stem and progenitor cells because of immune hyperactivity. Bone marrow mesenchymal stem cells (BMSCs) have hematopoietic supporting and immune regulation functions. This study investigated BMSCs homing in mice transplantation models after bone marrow failure. BALB/c mice were randomly divided into three groups: normal control, bone marrow failure model, and BMSC transplantation group. Chloromethyl benzamido-labeled BMSCs of BALB/c mice were transplanted through tail vein injection in mouse models with bone marrow failure. Flow cytometry and histological fluorescence microscopy were used to observe the dynamic distribution of labeled cells in different tissues. Average survival time, peripheral blood, and bone marrow morphological features were observed in mice from each group. Twenty-four hours after tail vein infusion of BMSCs, positively labeled cells were observed in the bone marrows of recipient mice, and the number of positive cells increased significantly at 72 h (P < 0.05). In dead or dying mice, white blood cells, hemoglobin, platelets, and bone marrow mononuclear cells were all significantly higher in the BMSC transplantation group than in the BMSCs of the model group (P < 0.01). Mean survival time was significantly shorter in the bone marrow failure model group than in the transplantation group (P < 0.05). These results confirmed that the major of BMSCs injected via tail vein could migrate to injured bone marrow tissues within 24-72 h in a mouse model of bone marrow failure. Furthermore, BMSCs can promote hematopoietic recovery, reduce the degree of bone marrow failure, and significantly prolong survival time.

Perisurgical induction of eculizumab in a patient with paroxysmal nocturnal hemoglobinuria: its inhibition of surgery-triggered hemolysis and the consequence of subsequent discontinuation.

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by complement (C')-induced lysis of PNH red blood cells (RBCs), which are deficient in the expression of CD55 and CD59. Surgery is one of the major clinical situations that trigger hemolytic attack and thrombosis in PNH. We describe here a case of 64-year-old man with classic PNH complicated by early-stage gastric cancer requiring distal gastrectomy under general anesthesia. We administered humanized monoclonal anti-C5 antibody (eculizumab; Soliris) for a limited period (600 mg, once a week × four times) perisurgically. Eculizumab effectively inhibited the C' system and the patient underwent a curative distal gastrectomy without significant surgery-triggered hemolytic attack. Although discontinuation of eculizumab induced mild hemolysis 2 weeks after the last administration, it was treated conservatively without thrombotic complication. Limited-term induction of eculizumab could be an option for PNH patients with transient and anticipated high risks, with careful preparation for the discontinuation-related risks afterwards.

Haematopoietic stem cell transplantation: activity in Switzerland compared with surrounding European countries.

Haematopoietic stem cell transplantation (HSCT) is a highly specialised procedure used to treat malignancies of the lymphohaematopoietic system as well as some acquired and inherited disorders of the blood. This analysis by the Swiss Blood Stem Cell Transplantation Group, based on data from 2008-2011, describes, treatment rates in Switzerland for specific indications and compares this with data from Germany, France, Italy and the Netherlands, corrected for the size of the population. Differences in transplant rates, in rates for particular indications, and in the use of specific transplant technologies such as use of unrelated donors, use of cord blood or mismatched family donors are described. These data are put in correlation with donor availability from international registries and with number of transplant teams and number of procedures per team all corrected for population size.

Last marrow standing: bone marrow transplantation for acquired bone marrow failure conditions.

Paroxysmal nocturnal hemoglobinuria, aplastic anemia, and myelodysplastic syndrome are a spectrum of acquired marrow failure, having a common pathologic thread of both immune dysregulation and the development of abnormal hematopoiesis. Allogeneic hematopoietic cell transplantation plays a critical role in the treatment of these disorders and, for many patients, is the only treatment modality with demonstrated curative potential. In recent years, there have been many breakthroughs in the understanding of the pathogenesis of these uncommon disorders. The subsequent advances in non-transplant therapies, along with concurrent improvement in outcomes after hematopoietic cell transplantation, necessitate continual appraisal of the indications, timing, and approaches to transplantation for acquired marrow failure syndromes. We review here contemporary and critical new findings driving current treatment decisions.

[Anesthetic management of a patient with paroxysmal nocturnal hemoglobinuria].

A 34-year-old man with paroxysmal nocturnal hemoglobinuria (PNH) was scheduled for emergency laparotomy. PNH is an acquired disorder of stem cells, and the common manifestations are complement mediated hemolytic anemia and deep venous thrombosis. Perioperative hemolysis occurs under the activation of complement induced by stress such as acidosis, infection, and insufficient pain control. Activation of complement secondary leads to platelet aggregation and hypercoagulability. We administrated remifentanil for the pain control during the operation and fentanyl after the operation. We avoided hypoventilation and dehydration to prevent acidosis. Washed red blood cells were given to reduce the chance of complement activation and we administrated low molecular weight heparin up to the seventh postoperative day to prevent deep venous thrombosis. The perioperative course was uneventful without complication.

Treatment of paroxysmal nocturnal hemoglobinuria in the era of eculizumab.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening and debilitating clonal blood disorder caused by an acquired mutation in the phosphatidylinositol glycan (PIG)-A gene. In pluripotent hematopoietic stem cells, this leads to a deficiency of glycosylphosphatidylinositol (GPI)-anchors and GPI-anchored proteins, including the complement regulators CD55 and CD59, on the surface of affected blood cells. PNH red blood cells are highly vulnerable to activation of complement and the formation of the membrane attack complex (MAC). The resulting chronic intravascular hemolysis is the underlying cause of PNH morbidities and mortality. Until recently, the treatment of PNH has been largely empirical and symptomatic with blood transfusions, anticoagulation, and supplementation with folic acid or iron. The only potentially curative treatment is allogeneic stem cell transplantation, but this has severe complications and high mortality and morbidity rates. A new targeted and disease-modifying treatment strategy is the inhibition of the terminal complement cascade with the humanized monoclonal anti-C5 antibody, eculizumab. This effectively inhibits MAC formation and intravascular hemolysis. Eculizumab has shown significant efficacy in controlled studies, with a marked decrease in anemia, fatigue, transfusion requirements, renal impairment, pulmonary hypertension, and risk of severe thromboembolic events, ultimately resulting in improving quality of life and survival.

[Anesthetic management of laparoscopic colon surgery in a patient with paroxysmal nocturnal hemoglobinuria].

This is a report of a patient with paroxysmal nocturnal hemoglobinuria (PNH) undergoing laparoscopic colon surgery. Preoperative examination showed pancytopenia, paroxysmal atrial fibrillation and slight renal function disorder. Heparin calcium was used to prevent venous thrombosis, because this case had several risk factors; advanced age, major surgery for cancer, PNH and long term medication with steroid. Washed red blood cells were transfused preoperatively. During the operation, total intravenous anesthesia was used. We prevented acidosis and other factors of thrombosis, and transfused washed red blood cells to correct anemia. During the postoperative course, red blood cells transfusion was required, but this case showed no obvious hemolysis, bleeding or venous thrombosis.

Hematopoietic stem cell transplantation for paroxysmal nocturnal hemoglobinuria: long-term results of a retrospective study on behalf of the Gruppo Italiano Trapianto Midollo Osseo (GITMO).

BACKGROUND: Paroxysmal nocturnal hemoglobinuria is an acquired clonal disorder of the hemopoietic stem cells for which the only curative treatment is allogeneic hematopoietic stem cell transplantation. DESIGN AND METHODS: The aim of this retrospective study was to assess the long-term clinical and hematologic results in 26 paroxysmal nocturnal hemoglobinuria patients who received hematopoietic stem cell transplantation in Italy between 1988 and 2006. The patients were aged 22 to 60 years (median 32 years). Twenty-three donors were HLA-identical (22 siblings and one unrelated) and 3 were HLA-mismatched (2 related and one unrelated). RESULTS: Fifteen patients received a myeloablative conditioning consisting of busulfan and cyclophosphamide (in all cases from identical donor) and 11 were given a reduced intensity conditioning (8 from identical donor and 3 from mismatched donor). The cumulative incidence of graft failure was 8% (4% primary and 4% secondary graft failure). Transplant-related mortality for all patients was 42% (26% and 63% for patients transplanted following myeloablative or reduced intensity conditioning, respectively). As of October 31, 2009, 15 patients (11 in the myeloablative conditioning group and 4 in the reduced intensity conditioning group) are alive with complete hematologic recovery and no evidence of paroxysmal nocturnal hemoglobinuria following a median follow-up of 131 months (range 30-240). The 10-year Kaplan-Meier probability of disease-free survival was 57% for all patients: 65% for 23 patients transplanted from identical donor and 73% for 15 patients transplanted with myeloablative conditioning. No thromboembolic event nor recurrence of the disease were reported following transplant. CONCLUSIONS: The findings of this study confirm that most patients with paroxysmal nocturnal hemoglobinuria may be definitively cured with hematopoietic stem cell transplantation.

[Eculizumab in paroxysmal nocturnal hemoglobinuria]. / Anticorps monoclonal anti-C5 (éculizumab) dans l'hémoglobinurie paroxystique nocturne.

Paroxysmal nocturnal hemoglobinuria is a rare acquired clonal of the hematopoietic stem cell due to acquired mutation of the PIG-A gene. This results in the lack of two GPI-anchored membrane proteins involved in the inhibition of complement attack, thus explaining red cells hemolysis. The development of an anti-C5 monoclonal antibody (eculizumab) had profoundly modified the treatment of the the hemolytic form of the disease.

Current status of allogeneic hematopoietic stem cell transplantation for paroxysmal nocturnal hemoglobinuria.

Treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) has been traditionally empirical, primarily aiming at ameliorating symptoms or treating complications resulting from the disease. Novel therapies such as eculizumab result in stabilization of hemoglobin levels and improvement in quality of life, but does not cure PNH. Nonrandomized studies suggest that long-term remissions are achievable when using myeloablative or nonmyeloablative/reduced-intensity (NMT/RIC) allogeneic hematopoietic stem cell transplantation (HSCT) as treatment for PNH. Nevertheless, patients with previous life-threatening complications from PNH may be more appropriately treated with an NMT/RIC regimen, rather than a myeloablative approach, because of the increased transplant mortality associated with the latter. The decision to perform an allogeneic HSCT (allo-HSCT) should weigh disease prognosis, by incorporating known adverse prognostic factors such as previous history of thrombosis and/or evolution to pancytopenia, among others, against the risk of transplant-related complications. Selection of the appropriate candidate and, equally important, the right time to perform an allo-HCT are important questions that need to be answered in the context of large prospective randomized trials.

HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide.

We evaluated the safety and efficacy of high-dose, posttransplantation cyclophosphamide (Cy) to prevent graft rejection and graft-versus-host disease (GVHD) after outpatient nonmyeloablative conditioning and T cell-replete bone marrow transplantation from partially HLA-mismatched (haploidentical) related donors. Patients with advanced hematologic malignancies (n = 67) or paroxysmal nocturnal hemoglobinuria (n = 1) received Cy 50 mg/kg i.v. on day 3 (n = 28) or on days 3 and 4 (n = 40) after transplantation. The median times to neutrophil (>500/microL) and platelet recovery (>20,000/microL) were 15 and 24 days, respectively. Graft failure occurred in 9 of 66 (13%) evaluable patients, and was fatal in 1. The cumulative incidences of grades II-IV and grades III-IV acute (aGVHD) by day 200 were 34% and 6%, respectively. There was a trend toward a lower risk of extensive chronic GVHD (cGVHD) among recipients of 2 versus 1 dose of posttransplantation Cy (P = .05), the only difference between these groups. The cumulative incidences of nonrelapse mortality (NRM) and relapse at 1 year were 15% and 51%, respectively. Actuarial overall survival (OS) and event-free survival (EFS) at 2 years after transplantation were 36% and 26%, respectively. Patients with lymphoid malignancies had an improved EFS compared to those with myelogenous malignancies (P = .02). Nonmyeloablative HLA-haploidentical BMT with posttransplantation Cy is associated with acceptable rates of fatal graft failure and severe aGVHD or cGVHD.